TY - JOUR
T1 - Amikacin combined with fosfomycin for treatment of neonatal sepsis in the setting of highly prevalent antimicrobial resistance
AU - Darlow, Christopher A.
AU - Docobo-Perez, Fernando
AU - Farrington, Nicola
AU - Johnson, Adam
AU - McEntee, Laura
AU - Unsworth, Jennifer
AU - Jimenez-Valverde, Ana
AU - Gastine, Silke
AU - Kolamunnage-Dona, Ruwanthi
AU - de Costa, Renata M.A.
AU - Ellis, Sally
AU - Franceschi, François
AU - Standing, Joseph F.
AU - Sharland, Mike
AU - Neely, Michael
AU - Piddock, Laura
AU - Das, Shampa
AU - Hope, William
N1 - Funding Information:
This work was funded the Global Antibiotic Research and Development Partnership (GARDP). The GARDP was funded by the German Federal Ministry of Education and Research, the German Federal Ministry of Health, Médecins Sans Frontières, the Netherlands Ministry of Health, Welfare, and Sport, the U.K. Department for International Development, and the U.K. National Institute of Health Research. C.A.D. is an MRC Clinical Training Fellow based at the University of Liverpool supported by the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the Medical Research Council (award reference no. MR/N025989/1), Roche Pharma, Eli Lilly and Company Limited, UCB Pharma, Novartis, the University of Liverpool, and the University of Manchester. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Publisher Copyright:
© 2021 American Society for Microbiology.
PY - 2021/7
Y1 - 2021/7
N2 - Antimicrobial resistance (particularly through extended-spectrum b-lactamase and aminoglycoside-modifying enzyme production) in neonatal sepsis is a global problem, particularly in low- and middle-income countries, with significant mortality rates. High rates of resistance are reported for the current WHO-recommended first-line antibiotic regimen for neonatal sepsis, i.e., ampicillin and gentamicin. We assessed the utility of fosfomycin and amikacin as a potential alternative regimen to be used in settings of increasingly prevalent antimicrobial resistance. The combination was studied in a 16-arm dose-ranged hollow-fiber infection model (HFIM) experiment. The combination of amikacin and fosfomycin enhanced bactericidal activity and prevented the emergence of resistance, compared to monotherapy with either antibiotic. Modeling of the experimental quantitative outputs and data from checkerboard assays indicated synergy. We further assessed the combination regimen at clinically relevant doses in the HFIM with nine Enterobacterales strains with high fosfomycin and amikacin MICs and demonstrated successful kill to sterilization for 6/9 strains. From these data, we propose a novel combination breakpoint threshold for microbiological success for this antimicrobial combination against Enterobacterales strains, i.e., MICF × MICA , 256 (where MICF and MICA are the fosfomycin and amikacin MICs, respectively). Monte Carlo simulations predict that a standard fosfomycin-amikacin neonatal regimen would achieve .99% probability of pharmacodynamic success for strains with MICs below this threshold. We conclude that the combination of fosfomycin with amikacin is a viable regimen for the empirical treatment of neonatal sepsis and is suitable for further clinical assessment in a randomized controlled trial.
AB - Antimicrobial resistance (particularly through extended-spectrum b-lactamase and aminoglycoside-modifying enzyme production) in neonatal sepsis is a global problem, particularly in low- and middle-income countries, with significant mortality rates. High rates of resistance are reported for the current WHO-recommended first-line antibiotic regimen for neonatal sepsis, i.e., ampicillin and gentamicin. We assessed the utility of fosfomycin and amikacin as a potential alternative regimen to be used in settings of increasingly prevalent antimicrobial resistance. The combination was studied in a 16-arm dose-ranged hollow-fiber infection model (HFIM) experiment. The combination of amikacin and fosfomycin enhanced bactericidal activity and prevented the emergence of resistance, compared to monotherapy with either antibiotic. Modeling of the experimental quantitative outputs and data from checkerboard assays indicated synergy. We further assessed the combination regimen at clinically relevant doses in the HFIM with nine Enterobacterales strains with high fosfomycin and amikacin MICs and demonstrated successful kill to sterilization for 6/9 strains. From these data, we propose a novel combination breakpoint threshold for microbiological success for this antimicrobial combination against Enterobacterales strains, i.e., MICF × MICA , 256 (where MICF and MICA are the fosfomycin and amikacin MICs, respectively). Monte Carlo simulations predict that a standard fosfomycin-amikacin neonatal regimen would achieve .99% probability of pharmacodynamic success for strains with MICs below this threshold. We conclude that the combination of fosfomycin with amikacin is a viable regimen for the empirical treatment of neonatal sepsis and is suitable for further clinical assessment in a randomized controlled trial.
KW - Amikacin
KW - Aminoglycosides
KW - Antimicrobial resistance
KW - Combination antibiotics
KW - Fosfomycin
KW - Hollow fiber
KW - Mathematical modelling
KW - Neonatal sepsis
KW - Pharmacodynamics
KW - Synergy
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U2 - 10.1128/AAC.00293-21
DO - 10.1128/AAC.00293-21
M3 - Article
C2 - 33972238
AN - SCOPUS:85108164380
VL - 65
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 7
M1 - e00293-21
ER -